Bottom Line:
Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance.In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor.These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

Objective: The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.

Research design and methods: We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype.

Results: Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3-specific lean phenotype was revealed on the standard diet.

Conclusions: These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

Mentions:
Glycemia was not different between genotypes on chow diet (Fig. 7A). However, double mutants had significantly lower blood glucose levels after 11–13 weeks on the HFD than Nestin-Cre mice. Socs-3 and Ptpn1 deletions had similar additive effects on lowering glucose levels (Fig. 7B). In addition, circulating insulin levels were lower in double mutants on standard diet and a trend toward low insulin levels on the HFD was observed (Fig. 7C and D). Interestingly, brain specific Socs-3 deletion accounted for the low insulinemia displayed by double mutants (Fig. 7C, two-way ANOVA). All together, these observations suggest that double mutants are more insulin sensitive than controls on both diets.

Mentions:
Glycemia was not different between genotypes on chow diet (Fig. 7A). However, double mutants had significantly lower blood glucose levels after 11–13 weeks on the HFD than Nestin-Cre mice. Socs-3 and Ptpn1 deletions had similar additive effects on lowering glucose levels (Fig. 7B). In addition, circulating insulin levels were lower in double mutants on standard diet and a trend toward low insulin levels on the HFD was observed (Fig. 7C and D). Interestingly, brain specific Socs-3 deletion accounted for the low insulinemia displayed by double mutants (Fig. 7C, two-way ANOVA). All together, these observations suggest that double mutants are more insulin sensitive than controls on both diets.

Bottom Line:
Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance.In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor.These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.

Objective: The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control.

Research design and methods: We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype.

Results: Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3-specific lean phenotype was revealed on the standard diet.

Conclusions: These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes.